c-Src tyrosine kinase mediates high glucose-induced endothelin-1 expression
| Autor: | Simona-Adriana Manea, Adrian Manea, Ioana Madalina Fenyo |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty 030204 cardiovascular system & hematology Biology Biochemistry Cell Line Diabetes Mellitus Experimental CSK Tyrosine-Protein Kinase Mice 03 medical and health sciences 0302 clinical medicine Western blot Downregulation and upregulation Internal medicine medicine Animals Humans Gene silencing Gene Silencing Protein Kinase Inhibitors Dose-Response Relationship Drug Endothelin-1 medicine.diagnostic_test Endothelial Cells Cell Biology Streptozotocin Endothelin 1 Cell biology Mice Inbred C57BL Glucose src-Family Kinases 030104 developmental biology Endocrinology Gene Expression Regulation Phosphorylation Tyrosine kinase Proto-oncogene tyrosine-protein kinase Src medicine.drug |
| Zdroj: | The International Journal of Biochemistry & Cell Biology. 75:123-130 |
| ISSN: | 1357-2725 |
| Popis: | Endothelin-1 (ET-1) plays an important role in the pathophysiology of diabetes-associated cardiovascular disorders. The molecular mechanisms leading to ET-1 upregulation in diabetes are not entirely defined. c-Src tyrosine kinase regulates important pathophysiological aspects of vascular response to insults. In this study, we aimed to elucidate whether high glucose-activated c-Src signaling plays a role in the regulation of ET-1 expression. Human endothelial cells EAhy926 (ECs) were exposed to normal or high levels of glucose for 24h. Male C57BL/6J mice were rendered diabetic with streptozotocin and then treated with a specific c-Src inhibitor (Src I1) or c-Src siRNA. Real-time PCR, Western blot, and ELISA, were used to investigate ET-1 regulation. The c-Src activity and expression were selectively downregulated by pharmacological inhibition and siRNA-mediated gene silencing, respectively. High glucose dose-dependently up-regulated c-Src phosphorylation and ET-1 gene and protein expression levels in human ECs. Chemical inhibition or silencing of c-Src significantly decreased the high-glucose augmented ET-1 expression in cultured ECs. In vivo studies showed significant elevations in the aortic ET-1 mRNA expression and plasma ET-1 concentration in diabetic mice compared to non-diabetic animals. Treatment with Src I1, as well as in vivo silencing of c-Src, significantly reduced the upregulated ET-1 expression in diabetic mice. These data provide new insights into the regulation of ET-1 expression in endothelial cells in diabetes. Pharmacological targeting of c-Src activity and/or expression may represent a potential therapeutic strategy to reduce ET-1 level and to counteract diabetes-induced deleterious vascular effects. |
| Databáze: | OpenAIRE |
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